Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H 1 receptor and TRPV1

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been impli...

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Bibliographic Details
Published in:American journal of physiology. Renal physiology 2020-02, Vol.318 (2), p.F298-F314
Main Authors: Grundy, Luke, Caldwell, Ashlee, Garcia Caraballo, Sonia, Erickson, Andelain, Schober, Gudrun, Castro, Joel, Harrington, Andrea M, Brierley, Stuart M
Format: Article
Language:English
Subjects:
Administration, Intravesical
Animals
Calcium Signaling - drug effects
Cells, Cultured
Cystitis, Interstitial - metabolism
Cystitis, Interstitial - physiopathology
Female
Ganglia, Spinal - drug effects
Ganglia, Spinal - metabolism
Ganglia, Spinal - physiopathology
Histamine - administration & dosage
Hyperalgesia - metabolism
Hyperalgesia - physiopathology
Male
Mechanoreceptors - drug effects
Mechanoreceptors - metabolism
Mechanotransduction, Cellular - drug effects
Mice, Inbred C57BL
Mice, Knockout
Pain Threshold - drug effects
Pressure
Receptors, Histamine H1 - drug effects
Receptors, Histamine H1 - metabolism
TRPV Cation Channels - deficiency
TRPV Cation Channels - genetics
TRPV Cation Channels - metabolism
Urinary Bladder - innervation
Urothelium - drug effects
Urothelium - metabolism
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Summary:Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited "silent afferents" that were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes ( - ) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, was the most abundantly expressed. Acute histamine exposure evoked Ca influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H receptor and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.00435.2019